Enhanced thymic selection of FoxP3+ regulatory T cells in the NOD mouse model of autoimmune diabetes
- Markus Feuerer*,
- Wenyu Jiang*,
- Phillip D. Holler*,
- Ansuman Satpathy*,
- Christopher Campbell*,
- Molly Bogue†,
- Diane Mathis*,‡, and
- Christophe Benoist*,‡
- *Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215; and
- †The Jackson Laboratory, Bar Harbor, ME 04609
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Contributed by Christophe Benoist, September 25, 2007 (received for review September 6, 2007)
Abstract
FoxP3+CD4+ regulatory T cells (Tregs) play a key role in the maintenance of peripheral self-tolerance, and it has been suggested that diabetes-susceptible nonobese diabetic (NOD) mice are defective in the generation and numbers of Tregs. We found thymic selection of Tregs to be under genetic control. Fetal thymic organ cultures on the NOD background required 3- to 10-fold more antigen than corresponding cultures on the B6 background for optimal induction of Tregs, but once the threshold for induction was reached the NOD background yielded close to 10-fold more Tregs. This increased selection of Tregs was also found in nontransgenic NOD mice in fetal through adult stages. This trait did not map to the MHC, idd3, or the chromosome 3 (Chr3) regions that control clonal deletion, but mainly to two regions on Chr1 and Chr11. Thus, NOD mice do not have a global defect in the generation or maintenance of Tregs; if anything, they show the opposite.
Footnotes
- ‡To whom correspondence should be addressed. E-mail: cbdm{at}joslin.harvard.edu
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Author contributions: M.F., W.J., P.D.H., A.S., C.C., D.M., and C.B. designed research; M.F., W.J., P.D.H., A.S., and C.C. performed research; M.B. contributed new reagents/analytic tools; M.F., W.J., P.D.H., A.S., and C.C. analyzed data; and M.F., D.M., and C.B. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0708899104/DC1.
- Abbreviations:
- NOD,
- nonobese diabetic;
- Treg,
- regulatory T cell;
- FTOC,
- fetal thymus organ culture;
- Chr(n),
- chromosome number;
- TCR,
- T cell receptor;
- CD4SP,
- CD4 single-positive;
- DP,
- double-positive;
- QTL,
- quantitative trait loci;
- E(n),
- embryonic day.
- © 2007 by The National Academy of Sciences of the USA
